Diversity and Complexity of the Large Surface Protein Family in the Compacted Genomes of Multiple Pneumocystis Species

ABSTRACT Pneumocystis, a major opportunistic pathogen in patients with a broad range of immunodeficiencies, contains abundant surface proteins encoded by a multicopy gene family, termed the major surface glycoprotein (Msg) gene superfamily. This superfamily has been identified in all Pneumocystis species characterized to date, highlighting its important role in Pneumocystis biology. In this report, through a comprehensive and in-depth characterization of 459 msg genes from 7 Pneumocystis species, we demonstrate, for the first time, the phylogeny and evolution of conserved domains in Msg proteins and provide a detailed description of the classification, unique characteristics, and phylogenetic relatedness of five Msg families. We further describe, for the first time, the relative expression levels of individual msg families in two rodent Pneumocystis species, the substantial variability of the msg repertoires in P. carinii from laboratory and wild rats, and the distinct features of the expression site for the classic msg genes in Pneumocystis from 8 mammalian host species. Our analysis suggests multiple functions for this superfamily rather than just conferring antigenic variation to allow immune evasion as previously believed. This study provides a rich source of information that lays the foundation for the continued experimental exploration of the functions of the Msg superfamily in Pneumocystis biology. IMPORTANCE Pneumocystis continues to be a major cause of disease in humans with immunodeficiency, especially those with HIV/AIDS and organ transplants, and is being seen with increasing frequency worldwide in patients treated with immunodepleting monoclonal antibodies. Annual health care associated with Pneumocystis pneumonia costs ∼$475 million dollars in the United States alone. In addition to causing overt disease in immunodeficient individuals, Pneumocystis can cause subclinical infection or colonization in healthy individuals, which may play an important role in species preservation and disease transmission. Our work sheds new light on the diversity and complexity of the msg superfamily and strongly suggests that the versatility of this superfamily reflects multiple functions, including antigenic variation to allow immune evasion and optimal adaptation to host environmental conditions to promote efficient infection and transmission. These findings are essential to consider in developing new diagnostic and therapeutic strategies.

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Immunodominant surface epitopes power immune evasion in the African trypanosome

10.1101/2021.07.20.453071 ◽

2021 ◽

Author(s):

Anastasia Gkeka ◽

Francisco Aresta-Branco ◽

Gianna Triller ◽

Evi P Vlachou ◽

Mirjana Lilic ◽

...

Keyword(s):

Immune Evasion ◽

Antigenic Variation ◽

Cross Reactivity ◽

Surface Glycoprotein ◽

Mammalian Host ◽

African Trypanosome ◽

Repetitive Nature ◽

Variable Surface ◽

Major Surface ◽

Immunodominant Epitopes

The African trypanosome survives the immune response of its mammalian host by antigenic variation of its major surface antigen (the Variable Surface Glycoprotein, or VSG). Here we describe the antibody repertoires elicited by different VSGs. We show that the repertoires are highly restricted, directed predominantly to epitopes on the surface of the VSGs. They are also highly discriminatory: minor alterations within these exposed epitopes confer antigenically-distinct properties to these VSGs and elicit different repertoires. We propose that the patterned and repetitive nature of the VSG coat focuses host immunity to a restricted set of immunodominant epitopes per VSG, eliciting a highly stereotyped response, minimizing cross reactivity between different VSGs and facilitating prolonged immune evasion through epitope variation.

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A Short-Term Borrelia burgdorferi Infection Model Identifies Tissue Tropisms and Bloodstream Survival Conferred by Adhesion Proteins

Infection and Immunity ◽

10.1128/iai.00349-15 ◽

2015 ◽

Vol 83 (8) ◽

pp. 3184-3194 ◽

Cited By ~ 23

Author(s):

Jennifer A. Caine ◽

Jenifer Coburn

Keyword(s):

Borrelia Burgdorferi ◽

Binding Protein ◽

The United States ◽

Surface Proteins ◽

Mammalian Host ◽

Infection Model ◽

Short Term ◽

Content Type ◽

Extracellular Matrix Components

Borrelia burgdorferi, the causative agent of Lyme disease in the United States, is able to persist in the joint, heart, skin, and central nervous system for the lifetime of its mammalian host.Borreliaspecies achieve dissemination to distal sites in part by entry into and travel within the bloodstream. Much work has been performedin vitrodescribing the roles of manyB. burgdorferiouter surface proteins in adhesion to host cell surface proteins and extracellular matrix components, although the biological relevance of these interactions is only beginning to be exploredin vivo. A need exists in the field for anin vivomodel to define the biological roles ofB. burgdorferiadhesins in tissue-specific vascular interactions. We have developed anin vivomodel of vascular interaction ofB. burgdorferiin which the bacteria are injected intravenously and allowed to circulate for 1 h. This model has shown that the fibronectin binding protein BB0347 has a tropism for joint tissue. We also have shown an importance of the integrin binding protein, P66, in binding to vasculature of the ear and heart. This model also revealed unexpected roles forBorreliaadhesins BBK32 and OspC in bacterial burdens in the bloodstream. The intravenous inoculation model of short-term infection provides new insights into criticalB. burgdorferiinteractions with the host required for initial survival and tissue colonization.

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Diversity and complexity of the large surface protein family in the compacted genomes of various Pneumocystis species

10.1101/814236 ◽

2019 ◽

Author(s):

Liang Ma ◽

Zehua Chen ◽

Da Wei Huang ◽

Ousmane H. Cissé ◽

Jamie L. Rothenburger ◽

...

Keyword(s):

Antigenic Variation ◽

Life Stage ◽

Surface Protein ◽

Opportunistic Pathogen ◽

Surface Proteins ◽

Surface Glycoprotein ◽

Mammalian Host ◽

Expression Site ◽

Phylogeny And Evolution ◽

Major Surface

AbstractPneumocystis, a major opportunistic pathogen in patients with a broad range of immunodeficiencies, contains abundant surface proteins encoded by a multi-copy gene family, termed the major surface glycoprotein (Msg) gene superfamily. This superfamily has been identified in all Pneumocystis species characterized to date, highlighting its important role in Pneumocystis biology. In this report, through a comprehensive and in-depth characterization of 459 msg genes from 7 Pneumocystis species, we demonstrate, for the first time, the phylogeny and evolution of conserved domains in Msg proteins, and provide detailed description of the classification, unique characteristics and phylogenetic relatedness of five Msg families. We further describe the relative expression levels of individual msg families in two rodent Pneumocystis species, the substantial variability of the msg repertoires in P. carinii from laboratory and wild rats, and the distinct features of the expression site for the classic msg genes in Pneumocystis from 8 mammalian host species. Our analysis suggests a wide variety of functions for this superfamily, not only conferring antigenic variation to allow immune evasion but also mediating life-stage development, optimizing cell mobility and adhesion, and adapting to specific host niches or environmental conditions. This study provides a rich source of information that lays the foundation for the continued experimental exploration of the functions of the Msg superfamily in Pneumocystis biology.

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EU may struggle to enforce social standards via trade

Emerald Expert Briefings ◽

10.1108/oxan-db259958 ◽

2021 ◽

Keyword(s):

United States ◽

The United States ◽

Environmental Standards ◽

Content Type ◽

Social Standards ◽

Investment Agreement ◽

Trade Deals ◽

First Time ◽

Trade Partners ◽

The Eu

Significance In 2020 the European Commission appointed a Chief Trade Enforcement Officer for the first time, signalling that Brussels is intent on enhancing its capacity to enforce standards agreed in trade deals. However, the EU's experience with South Korea suggests that holding trade partners to account over breaching standards will be difficult. Impacts Relations with trade partners could deteriorate if the EU is seen to be aggressive in enforcing its standards. Concern over China’s willingness to improve labour and environmental standards could impede ratification the EU-China investment agreement. The EU may be reluctant to sanction some partners, such as the United States, that breach labour or environmental standards.

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New Zealand White Rabbits Effectively ClearBorrelia burgdorferiB31 despite the Bacterium’s FunctionalvlsEAntigenic Variation System

Infection and Immunity ◽

10.1128/iai.00164-19 ◽

2019 ◽

Vol 87 (7) ◽

Cited By ~ 1

Author(s):

Maliha Batool ◽

Andrew E. Hillhouse ◽

Yurij Ionov ◽

Kelli J. Kochan ◽

Fatemeh Mohebbi ◽

...

Keyword(s):

New Zealand ◽

Persistent Infection ◽

Antigenic Variation ◽

Surface Expression ◽

The United States ◽

Antimicrobial Treatment ◽

Current Data ◽

Content Type ◽

Highly Evolved

ABSTRACTBorrelia burgdorferiis a tick-borne bacterium responsible for approximately 300,000 annual cases of Lyme disease (LD) in the United States, with increasing incidences in other parts of the world. The debilitating nature of LD is mainly attributed to the ability ofB. burgdorferito persist in patients for many years despite strong anti-Borreliaantibody responses. Antimicrobial treatment of persistent infection is challenging. Similar to infection of humans,B. burgdorferiestablishes long-term infection in various experimental animal models except for New Zealand White (NZW) rabbits, which clear the spirochete within 4 to 12 weeks. LD spirochetes have a highly evolved antigenic variationvlssystem, on the lp28-1 plasmid, where gene conversion results in surface expression of the antigenically variable VlsE protein. VlsE is required forB. burgdorferito establish persistent infection by continually evading otherwise potent antibodies. Since the clearance ofB. burgdorferiis mediated by humoral immunity in NZW rabbits, the previously reported results that LD spirochetes lose lp28-1 during rabbit infection could potentially explain the failure ofB. burgdorferito persist. However, the present study unequivocally disproves that previous finding by demonstrating that LD spirochetes retain thevlssystem. However, despite thevlssystem being fully functional, the spirochete fails to evade anti-Borreliaantibodies of NZW rabbits. In addition to being protective against homologous and heterologous challenges, the rabbit antibodies significantly ameliorate LD-induced arthritis in persistently infected mice. Overall, the current data indicate that NZW rabbits develop a protective antibody repertoire, whose specificities, once defined, will identify potential candidates for a much-anticipated LD vaccine.

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Environment and technology dominate the WEF agenda

Emerald Expert Briefings ◽

10.1108/oxan-db217325 ◽

2017 ◽

Keyword(s):

Climate Change ◽

Large Scale ◽

The United States ◽

Extreme Weather Events ◽

Content Type ◽

Mitigation And Adaptation ◽

The People ◽

Impact Risk ◽

Trade Deals ◽

First Time

Significance For the first time in the eleven-year history of the survey, no economic risk makes the list of the top five most likely or biggest impact risks. In contrast, large-scale terrorist attacks make the top five most likely risks for the first time and weapons of mass destruction are cited as the highest impact risk. All five environment-related risks are ranked among the top ten highest impact risks for the first time -- four in the top five: extreme weather events; water crises; major natural disasters; and failure of climate change mitigation and adaptation. The survey cites strengthening global cooperation systems as a top five challenge, and says these environmental risks will be exacerbated if cooperation diminishes. Impacts Nearly a third of respondents think that increasing polarisation will be an underlying trend over the next ten years. More must be done to include the people left behind by technological change -- more than 4 billion lack internet access. The United States may withdraw from the Paris climate change agreement, and a number of free trade deals are at risk.

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Taiwan’s profile rises amid China-US tensions

Emerald Expert Briefings ◽

10.1108/oxan-db252978 ◽

2020 ◽

Keyword(s):

United States ◽

International Aid ◽

The United States ◽

World Health ◽

International Organisations ◽

Content Type ◽

World Health Assembly ◽

State Security ◽

The World ◽

First Time

Subject The outlook for China-Taiwan relations. Significance Taiwan’s China-sceptic government is benefiting from its spectacular success against COVID-19, Western support for its participation in the World Health Assembly against Beijing’s wishes and China's recent decision to let state security agents operate openly in Hong Kong for the first time -- a move that undermines the city’s promised autonomy. Impacts Taiwan’s international aid for battling COVID-19 will build support from key partners, especially the United States and European countries. China will block Taiwan’s participation in international organisations at any level during Tsai’s second term. As Taiwan focuses on unofficial relationships with major democracies, China will continue to whittle away at Taiwan’s official allies.

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An Ecotype of Neorickettsia risticii Causing Potomac Horse Fever in Canada

Applied and Environmental Microbiology ◽

10.1128/aem.01366-16 ◽

2016 ◽

Vol 82 (19) ◽

pp. 6030-6036 ◽

Cited By ~ 3

Author(s):

Qingming Xiong ◽

Hannah Bekebrede ◽

Pratibha Sharma ◽

Luis G. Arroyo ◽

John D. Baird ◽

...

Keyword(s):

United States ◽

South America ◽

The United States ◽

Amino Acid Sequences ◽

Surface Proteins ◽

New Method ◽

Fatal Disease ◽

Content Type ◽

Strain Diversity ◽

Potomac Horse Fever

ABSTRACTNeorickettsia(formerlyEhrlichia)risticiiis an obligatory intracellular bacterium of digenetic trematodes. When a horse accidentally ingests aquatic insects containing encysted trematodes infected withN. risticii, the bacterium is transmitted from trematodes to horse cells and causes an acute and often fatal disease called Potomac horse fever (PHF). Since the discovery ofN. risticiiin the United States in 1984, using immunofluorescence and PCR assays, PHF has been increasingly recognized throughout North America and South America. However, so far, there exist only a few stableN. risticiiculture isolates, all of which are from horses within the United States, and the strain diversity and environmental spreading and distribution of pathogenicN. risticiistrains remain poorly understood. This paper reports the isolation ofN. risticiifrom the blood of a horse with acute PHF in Ontario, Canada. IntracellularN. risticiicolonies were detected in P388D1cells after 47 days of culturing and 8 days after the addition of rapamycin. Molecular phylogenetic analysis based on amino acid sequences of major surface proteins P51 and Ssa1 showed that this isolate is distinct from any previously sequenced strains but closely related to midwestern U.S. strains. This is the first Canadian strain cultured, and a new method was developed to reactivate dormantN. risticiito improve culture isolation.IMPORTANCENeorickettsia risticiiis an environmental bacterium that lives inside flukes that are parasitic to aquatic snails, insects, and bats. When a horse accidentally ingests insects harboring flukes infected withN. risticii, the bacterium is transmitted to the horse and causes an acute and often fatal disease called Potomac horse fever. Although the disease has been increasingly recognized throughout North and South America,N. risticiihas not been cultured outside the United States. This paper reports the first Canadian strain cultured and a new method to effectively culture isolateN. risticiifrom the horse blood sample. Molecular analysis showed that the genotype of this Canadian strain is distinct from previously sequenced strains but closely related to midwestern U.S. strains. Culture isolation ofN. risticiistrains would confirm the geographic presence of pathogenicN. risticii, help elucidateN. risticiistrain diversity and environmental spreading and distribution, and improve diagnosis and development of vaccines for this dreadful disease.

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Antibodies to Borrelia burgdorferi OspA, OspC, OspF, and C6 Antigens as Markers for Early and Late Infection in Dogs

Clinical and Vaccine Immunology ◽

10.1128/cvi.05653-11 ◽

2012 ◽

Vol 19 (4) ◽

pp. 527-535 ◽

Cited By ~ 32

Author(s):

Bettina Wagner ◽

Heather Freer ◽

Alicia Rollins ◽

David Garcia-Tapia ◽

Hollis N. Erb ◽

...

Keyword(s):

Lyme Disease ◽

Borrelia Burgdorferi ◽

The United States ◽

Sensu Stricto ◽

Antibody Responses ◽

Surface Proteins ◽

Early Infection ◽

Enzyme Linked Immunosorbent Assay ◽

Content Type ◽

Antibody Levels

ABSTRACTLyme disease in the United States is caused byBorrelia burgdorferisensu stricto, which is transmitted to mammals by infected ticks.Borreliaspirochetes differentially express immunogenic outer surface proteins (Osp). Our aim was to evaluate antibody responses to Osp antigens to aid the diagnosis of early infection and the management of Lyme disease. We analyzed antibody responses during the first 3 months after the experimental infection of dogs using a novel multiplex assay. Results were compared to those obtained with two commercial assays detecting C6 antigen. Multiplex analysis identified antibodies to OspC and C6 as early as 3 weeks postinfection (p.i.) and those to OspF by 5 weeks p.i. Antibodies to C6 and OspF increased throughout the study, while antibodies to OspC peaked between 7 and 11 weeks p.i. and declined thereafter. A short-term antibody response to OspA was observed in 3/8 experimentally infected dogs on day 21 p.i. Quant C6 enzyme-linked immunosorbent assay (ELISA) results matched multiplex results during the first 7 weeks p.i.; however, antibody levels subsequently declined by up to 29%. Immune responses then were analyzed in sera from 125 client-owned dogs and revealed high agreement between antibodies to OspF and C6 as robust markers for infection. Results from canine patient sera supported that OspC is an early infection marker and antibodies to OspC decline over time. The onset and decline of antibody responses toB. burgdorferiOsp antigens and C6 reflect their differential expression during infection. They provide valuable tools to determine the stage of infection, treatment outcomes, and vaccination status in dogs.

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Staphylococcus aureus Protein A Promotes Immune Suppression

mBio ◽

10.1128/mbio.00764-13 ◽

2013 ◽

Vol 4 (5) ◽

Cited By ~ 34

Author(s):

Scott D. Kobayashi ◽

Frank R. DeLeo

Keyword(s):

Staphylococcus Aureus ◽

B Cell ◽

Immune Evasion ◽

Bacterial Infections ◽

Binding Capacity ◽

Protein A ◽

Strong Support ◽

The United States ◽

Content Type

ABSTRACTStaphylococcus aureusis a prominent cause of human infections worldwide and is notorious for its ability to acquire resistance to antibiotics. Methicillin-resistantS. aureus(MRSA), in particular, is endemic in hospitals and is the most frequent cause of community-associated bacterial infections in the United States. Inasmuch as treatment options for severe MRSA infections are limited, there is need for a vaccine that protects against such infections. However, recent efforts to generate a staphylococcal vaccine have met with little success in human clinical trials. These failures are somewhat puzzling, since the vaccine antigens tested promote opsonophagocytosisin vitroand confer protection in animal infection models. One possibility is that the pathogen inhibits (and/or fails to elicit) the development of protective immunity in humans. Indeed,S. aureusproduces numerous molecules that can potentially promote immune evasion, including protein A (SpA), an immunoglobulin (Ig)-binding protein present on the bacterial surface and freely secreted into the extracellular environment. SpA binds the Fc region of antibody and the Fab regions of the B-cell receptor, processes that are known to block opsonophagocytosis and cause B-cell deathin vitro. In a recent study, Falugi et al. [F. Falugi, H. K. Kim, D. M. Missiakas, and O. Schneewind, mBio 4(5):e00575-13, 2013] showed that vaccination withspamutantS. aureusstrains lacking antibody Fc- and/or Fab-binding capacity protects against subsequent challenge with the USA300 epidemic strain. The findings provide strong support for the idea that SpA promotesS. aureusimmune evasionin vivoand form the foundation for a new approach in our efforts to develop a vaccine that prevents severeS. aureusinfections.

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